The pathophysiology of sickle cell disease originates in the polymerization of sickle hemoglobin. Fetal hemoglobin (HbF) inhibits this process, and high HbF concentrations reduce the severity of the disease. Drugs with presumed mechanisms of action that perturb the orderly maturation of erythroid precursor cells, induce hypomethylation of HbF genes, bind transcriptionally active elements of these genes, or influence chromatin structure can enhance HbF production in sickle cell disease. Hydroxyurea, a drug that affects erythroid maturation and regeneration, reduces morbidity and mortality in adults with sickle cell anemia. Its use in young children and in combination with other classes of HbF-inducing agents is being studied.